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Lupus and the Disappearing Regulatory B Cells

Lupus is a “mysterious” rheumatic autoimmune disease—the immune system attacks the body’s own healthy tissues, causing damage to the skin, joints, kidneys and many other organs. Such damage is mostly the result of excessive inflammation and production of antibodies, called auto-antibodies, against the body’s own tissues. Lupus is sometimes called the “great imitator,” because people often confuse the disease with other health problems—its wide range of symptoms are indeed common to many other disorders.

While some people with lupus suffer only minor inconvenience, others suffer significant lifelong disability. The signs of lupus vary depending on which body systems are affected by the disease. Fatigue and fever, joint pain, stiffness and swelling, are some of the most common symptoms. No two cases of lupus are exactly alike: signs and symptoms may come on suddenly or develop slowly, may be mild or severe, and may be temporary or permanent. Most people with lupus have mild disease characterized by episodes—called flares—when signs and symptoms get worse for a while, then improve or even disappear completely for a time.

Lupus affects people of African, Asian, or Native American descent two to three times as often as it affects whites. Nine out of 10 people with lupus are women. The disease usually strikes between age 15 and 44, although it can occur in older individuals. No single factor is known to cause lupus—rather, a combination of genetic, hormonal, environmental, and immune system factors appears to be behind it.

Now, results from a new study reveal the potential molecular mechanisms at the basis of the excessive inflammation and auto-antibody production involved in the development of lupus. The study (A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus) was carried out using human blood samples to isolate, compare and characterize different types of B cells present in healthy individuals and lupus patients. The investigators found that regulatory B cells, which in healthy individuals suppress immune responses and prevent inflammation, are not present in patients with lupus as a result of miscommunication between different cell types—B cells that produce antibodies, plasmacytoid dendritic cells that produce the cytokine interferon-alpha which functions to stimulate B cells, and regulatory B cells that suppress excessive immune responses.

Claudia Mauri, senior author of the study, said in a press release: “Our study shows for the first time that the overproduction of IFN-alpha by hyperactivated plasmacytoid dendritic cells in lupus patients is the consequence of the lack of suppressive regulatory B cells. The uncontrolled production of IFN-alpha causes an increase of antibody-producing B cells and suppresses the division and appearance of regulatory B cells.”

In their paper, the authors conclude that modulating the interactions between plasmacytoid dendritic cells and regulatory B cells could potentially create new opportunities for the development of immune-based therapies to treat patients with lupus.

11 comments

As mentioned by the researchers, knowing the details of the relationship between regulatory B cells, IFN-α and the cells like plasmacytoid dendritic cells that secrete IFN-α, will help develop a treatment for lupus. In the study, the researchers observed the effects of the cancer drug rituximab in patients with systemic lupus erythematous. Rituximab is included in chemotherapy for B-cell malignant cancers and has the ability to induce tumor cell death and block signaling in between malignant cells. The results of the study showed that patients who responded to the drug had decreased plasmacytoid dendritic cell activation, meaning less IFN-α secreted and decreased inflammation, and close to normal regulatory B-cell function. Although this drug was not specifically developed for lupus patients, the results of this study provides a foundation for development of a variation of the drug or more research into its effects on lupus patients.

I agree with you in regards to the potentially positive therapeutic effects of the rituximab drug for lupus patients. However, after research into the drug, past research suggest that its main mechanism of treatment is through B-cell depletion. In contrast, this particular article states that rituximab may have a role in normalizing the balance between pDc cells and regulatory B cells, leading to a decrease in the IFN-alpha secretion. It would be very interesting to know if both mechanisms contribute to the ease of symptoms for this autoimmune disease or whether one mechanism is more prevalent than the other.

You mention the possibility of a variation of the drug. I believe that this may be a good idea and worth researching. If researchers can find a way to shift the activity to one mechanism or the other than maybe the administration of this new drug could possibly be more effective and specific to each individual case of lupus. Furthermore, one of our fellow classmates mentioned that no two cases of lupus are exactly alike. Therefore, it could be beneficial to study a treatment containing a more specific/targeted approach to increasing regulatory B-cell activity and decreasing pathogenic B cell activity.

As the article stated, the unregulated production of IFN-α can cause the symptoms of Lupus due to regulatory plasma cells being unable to communicate with plasmacytoid dendritic cells (pDC). Nearly every cell type in the body can release type I IFNs, which includes IFN-α, but pDCs are unique in that they specialize in releasing massive amounts of IFN-α (1). This unchecked release of IFN-α is believed to play a pivitol role in the pathogenesis of Lupus, and another study that was recently published has found that IgE antibodies actually down-regulate the release of IFN-α from pDCs. They also found that subjects who did not have Lupus, or were not showing symptoms of Lupus, had much higher levels levels of IgE than those with Lupus (2). Given the insights from these two articles, perhaps the communication breakdown between regulatory B cells and pDCs may be caused by a diminished release of IgE from regulatory B cells. That may be a good starting point for future research.

Having known somebody with Lupus, this research and finding really intrigue me. First of all, Lupus is an autoimmune disease, a disease in which your immune system cannot tell the different between foreign invaders and your own body tissue, therefore your immune system will create autoantibodies that attack and destroy body’s healthy tissue. Research estimate that over 1.5 million of American have lupus, and as the article have mentions, out of that 1.5 million 9 out of 10 are women. This is quite a large number. The article also mentions that “no two case of lupus are exactly alike”, this show that lupus is a complex disease and each clinical manifestation will need a unique treatment approach. For the close friend that has lupus, she has to take Prednisone every day, and this medication has a lot of side effect.
I believe that this study may just play just bring about some new idea regarding Lupus management. This study emphasizes that the miscommunication between B cell that produces antibodies, plasmacytoid dendritic cells and regulatory B cells that caused an unregulated immune response. With this knowledge, I believe that we could definitely come up with a new approach to lupus treatment. Perhaps a treatment approach that regulates interferon A produced by plasmacytoid dendritic cells. I’m looking forward to seeing if there will be a new drug or treatment that could come to this…so that my friend doesn’t have to constantly take prednisone every day.

The blog mentions a study involving human blood samples that were compared and characterized from healthy patients and patients with lupus. The study mentions that the distinguishing factor of the blood of patients with is lupus is the absence of regulatory B cells. As stated regulatory B cells are key in suppressing immune responses and preventing inflammation. The link to the study describes how regulatory B cells are able to do this via the release of IL-10, transforming growth factor (TGF)-β, and IL-35. My question is even though regulatory B cells are absent in patients with lupus aren’t there other cells that can release IL-10? Upon further research there are other cells such as effector Th1 cells that can release IL-10 and limit the excessive inflammation that is associated with lupus. As far as IL-35 goes other cells such as T regulatory cells can release IL-35 as well. Wouldn’t the release of these cytokines suppress the excessive inflammation no matter what kind of cell produces it? Also the blog mentioned that nine out of ten people with lupus are women. To me that was shocking. I don’t understand why lupus is much more common in women than in men. The blog does mention that genetics is one possible factor that causes lupus. There is one study that expounds upon the genetic factor. The study suggests that men need to acquire a greater number of genetic risk factors in order for them to have lupus. Since men have a higher threshold of genetic risk they are less likely to have lupus than women.

Patrick,
The questions that you’ve raised are very thought provoking. Now that you have made the point that other immune cells can produce IL-10, I too wonder why this same IL-10 could not be used to control the inflammatory response. From my article I referenced in my previous comment and your article, they both agree that IL-10 down regulates T cells. As I could not find any research specific relating to your question, I can only hypothesize that perhaps B cells release IL-10 more abundantly than other cells of the immune system. The absence of it causes T cells to be overactive. Maybe this contributes to the chronic inflammation in lupus. A prolonged immune response by any cell is not a good thing and can be damaging.
In terms of the second part of your question, I believe this is still an ongoing area of research in which there is no absolutely correct answer at the moment. In general, I found that most autoimmune disorders are in women. This is not just limited to lupus, but also Graves disease, multiple sclerosis, and rheumatoid arthritis. Some reasons why they believe this occurs is because women naturally have stronger inflammatory responses than men, hormonal fluctuations in women that is experienced with menstruation and pregnancy, and inheritance of two x chromosomes ( as compared to a man’s 1) with defects related to inflammation. I think you will find this interesting, and the link is below for more detail if you’d like.

Through experimentation in ” “ the authors suggest an “auto”-regulatory feedback mechanism to describe the development of regulatory b cells through interactions with plamacytoid dendritic cells (pDCs), ultimately converting immature b cells into regulatory B cells. The article states that, in healthy individuals, pDCs drive this conversion through the release of IFN-alpa and CD40. In contrast, individuals with systemic lupus lack the communication between pDCs and regulatory B cells. This miscommunication leads to a lack of B regulatory cell mediated immune suppression, which is critical for the reduction of both inflammation and the production of autoantibodies (pathogenic). The authors go even further to show that a significant increase in pDCs IFN-alpha secretion in healthy individuals can lead to the defect (miscommunication, etc) previously mentioned. In addition, the authors determine a regulatory feedback mechanism which is cultivated by the release of IL-10 from the regulatory B cells, which act on the pDC cells and decrease the production of IFN-alpha. Therefore, the authors concluded that therapeutic innervation of the pDC and regulatory B cell interaction has major implication for treatment of systemic lupus.

In the article, the authors discuss a causative (dependent) relationship between pDC INF-alpha secretion and regulatory B cell IL-10 secretion, claiming that the release of IL-10 from regulatory B cells actually decreases the secretion of INF-alpha from the pDCs. The authors also discuss the therapeutic effects of the drug rituximab, and state that “patients responding to rituximab display a normalized pDC-Breg cell interaction”. According to the article, “B-Cell Depletion with Rituximab in Relapsing–Remitting Multiple Sclerosis”, rituximab is an antibody which depletes B-cells within the body and is used to treat cancers and autoimmune disorders. Therefore, it might be concluded that the positive response seen by patients responding to rituximab is could be due to a decrease in overall pathogenic autoantibody producing plasma cells. The authors briefly mention this fact within the results, but emphasize that rituximab might normalize the interaction between pDCs and regulatory B cells. Do you think that the positive effects of rituximab ¬¬is due to the normalization of pDC/Regulatory B cell interaction or pathogenic B-cell depletion? I would like to see another research article evaluating the two mechanisms of rituximab and determining which is most prevalent method seen in relieving the negative effects seen in lupus.

Reading the study and article reminds me of a question that we had on a test in which we had to choose one cell of the immune system that a mutant mice may lack. I chose to have the mouse do without the B cells. Now, reading this I understand how a lack of B cells, specifically regulatory B cells, can affect the immune system. Since I am not very familiar with the role of regulatory B cells, I stumbled upon an article that coincided with the research that without B regulatory cells, inflammation did increase. The article also provided interesting information that B regulatory cells could promote tumor growth in our cells. The reason for this, according to the research, was that the immunosuppressive activity of B regulatory cells in controlling inflammation is the same mechanism that inhibits cytotoxic T cells. I found this very interesting. Essentially, the research is indicating a lack of Breg cells limit tumor formation. So, are those with lupus at less risk of developing cancer due to a lack of B reg cells? We live in a world with conflicting information that tells us one thing is good and other is bad. I looked into another study and learned that a lack of B cells can also cause recurrent infections of the respiratory tract, like pneumonia and bronchitis. Despite the study, I would prefer my B cells. I think what the previous study has discovered is interesting, but also dangerous considering that cancer is a very scary word in our society. I personally think that there are much bigger things at fault for cancer than B reg cells promoting tumor production, but that is another conversation.

While the article above mentions the fact that Lupus is developed due the lack of regulatory B cells which provokes inflammation and auto-antibodies production, Lupus can be caused by other things such as hormones, genetics and it explains why women are more likely to get the disease more often than men.
The article that I found state that because women have an extra X chromosome, even though it is silenced, some of the genes from that X chromosomes are still working. As a result, women express more genes from the X chromosome than men, and those genes play a role in immunity. Also, because women carry a foreign body inside them during pregnancy, they exchange their genes. The exchange is supposed to be cleared after the pregnancy but sometimes it is not cleared at 100%, and that can mess with their immune system ability to make a difference between what is self and what is foreign. Finally, regarding hormones, despite the fact that both men and women produce estrogen, women tend to produce more of it, and estrogen boosts the body response to infection.
Therefore, lupus is also caused due to genetics and hormones and all the information above explains why women tend to have it more than men. Could the environment be also a cause of Lupus?

Regulatory B cells (Bregs) function by producing IL-10 which is inhibits pro-inflammatory cytokines like IL-2, IFN-ɣ and TNF-ɑ. They also inhibit T helper and dendritic cell function and unlike regular B cells can respond directly to antigens rather than needing a Th cell. They represent a small percentage of the B cells in the body (<0.5%) but their absence would lead to uncontrolled auto-inflammation i.e. autoimmune diseases like Lupus.
According to Claudia Mauri, Lupus is as a result of hyperactivated plasmacytoid dendiric cells leading to the overproduction of TNF-ɑ as a result of no Bregs. This fact had me consider possible methods of treatment rather than just corticosteroid administrations to reduce symptoms. Could the transfer of activated Bregs from an adapted individual to a Lupus patient be possible? Lupus being autoimmune and no two cases being the same might be a hindrance as each person could be reacting to a different auto-antigen but research has been done on this and it was discovered that the adoptive transfer of these activated Bregs led to the production of TGF-β which increased Treg production. It also induced apoptosis of TH1 cells and the inhibition of antigen-presentation of these cells thus effectively reducing TNF-ɑ .
I think more research should definitely be done in this area as the experiment by Lee, K. et al showed positive results and tested the hypothesis of Adoptive Breg transfer promote tolerance thus could lead to a cure for Lupus.